Significant advances have come rapidly in both our knowledge of, as well as potential uses for, mammalian stem cells of embryonic origin, umbilical cord stem cells, and undifferentiated or pluripotent cells found in all adult human tissues. Around this knowledge a series of new disciplines are gaining acceptance known as regenerative medicine, cell therapy, and cell medicine, among others. With improved understanding there is increasing positive acceptance and confidence in the therapeutic potential of these new and unique treatment strategies by the population. Turning all of these expectations into reality, however, involves long, complex, and expensive interventions.
Cells capable of differentiation and expansion into many or any tissue or organ can be found in adult or embryonic tissue. These “stem cells” are present in both plants and animals. Stem cells can also be created by a process called de-differentiation of adult somatic cells.
All plant cells, if exposed to adequate conditions and specific stimuli, are capable of transforming, into embryonic tissue (formation of callus). Under the right conditions, these cells have the ability to regenerate a complete individual. This attribute of plant cells has been extensively studied since Steward's pioneering efforts at Cornell University in 1958 termed somatic embryogenesis (1).
In June 2007, forty-nine years after the discovery of somatic embryogenesis in plants, S. Chen described a similar process in mammalian cells and named it de-differentiation. Chen observed that cardiac cells (myoblasts) could be induced to de-differentiate into osteoblasts and adipocytes using a purine derivative called “reversine” (3, 4, 5, 6).
Stem cells are also found naturally present in adult tissue. Animal stem cells have the ability to renew themselves or multiply and remain undifferentiated or the stem cells can differentiate into other cell populations. Re-populating hematopoietic stem cells (HSCs) have been identified in mouse bone marrow (14).
Embryonic stem cells were identified in studies by Thomson in 1995 and Shamblot in 1998 (15, 16). Subsequently, Thomson (17) and Gearhart (18) independently described the characteristics and potential attributes of human embryonic stem cells. Numerous reviews and articles on human stem cells have been written (19, 20, and 21), and recently some reports of studies of plant stem cells (22, 23, and 24) have been published.
In plants, meristems or meristematic cells have the ability to regenerate an entire individual (plant) under the influence of auxins/cytokinins using different in vitro, as well as ex vitro, manipulations. The meristems are a group of undifferentiated cells located mainly in the upper (apical) portion of the plant; sometimes they can also be found in roots. These cells known as “plant stem cells” are believed to possess characteristics similar to animal stem cells (26, 27).
Plant stem cells can be quiescent (dormant) at certain times or be activated to divide. The quiescence or activation of stem cells is modulated by shifting balances in the plant hormone signals from their niche. Once the stem cells have divided, the daughter cells receive yet additional plant hormone signals to differentiate, thereby diminishing or abolishing any further cell division.
In plant and tissue culture laboratories, plant stem cells are made to reproduce continually using compounds known as auxins (i.e., 3-indolyl-acetic acid (IAA), 2,4-D dichlorophenoxyacetic acid (2) and cytokinins (kinetin or 6-furfurylaminopurine). Under the influence of auxins, plant tissues form a multicellular balloon-like structure known as a “callus”; the cells of the callus can disperse in liquid growth media. Under proper growth conditions of temperature, asepsis, nutrition, light, and air, the cells will multiply and can be “directed” to differentiate.
Adult plant cells cell can also be made to multiply or differentiate into complete individuals with reproductive organs. Millions of replicas can be easily obtained and transformed into complete individuals (clones) from one or a few undifferentiated plant (meristematic cells). This natural phenomenon is used on a large scale for the production of millions of plant clones and constitutes a procedure of great scientific and economic value, specifically in the citrus (7) and wood (8, 9) industries. Interestingly, development of the pre-embryonic or embryonic tissue (callous formation) is induced by either the cytokinin 6-benzylaminopurine (BAP) or an auxin called 2,4 dichlorophenoxyacetic acid (2,4 D). The differentiation process is optionally induced by increasing the osmotic potential of the growth media. In plant tissue culture, other procedures are also commonly used, such as organogenesis, which involves taking the initial material from a bud or sprout.
The presence of stem cells is now recognized in most eukaryotes, including plants, fungi, alveolates, red algae, moulds, and animals, including humans. Most, if not all, laboratories working with mammalian stem cells use proteins to study growth and differentiation. However, low molecular weight biomodulators are not understood, and represent an innovative approach to solving problems in a new and dynamic biological field.
The term biomodulators describes greater than 150 compounds known that influence the growth and differentiation of plant cells and tissues. Most biomodulators are of low molecular weight. Some effects of biomodulators were described in plants by Bonner (77). An important number of basic cell and tissue functions are present and similar in both plants and animals. However, only recently have we begun to understand their common origin and similarities at the molecular level.
The study of biomodulators has an important practical and economic impact since relevant research is performed with crystalline substances that are easy to handle and store, readily available, and inexpensive, which may balance historical research that has been skewed towards genomics and proteomics (78).
The uncontrolled and exponential growth often found in mammals as cancer, with frequently lethal consequences, does not occur frequently in plants. An exception is some rare, benign, superficial outgrowths of bacterial, fungal or viral origin [for a review, see Bayer et al. (79)]. On the contrary, in plants regulated growth continues until the end of the plant life cycle as seen in the Bristlecone pines of California that are claimed to be 4770 years old. Their continued presence may represent a significant task for their “plant stem cells” (80). Death in plants is mostly observed in response to external factors such as drought, fire, or simply collection or harvest.
Many scientists concerned with mammalian cancer are focusing on “stem cells, cancer, and cancer stem cells” such as Reya (81) and others (82, 83). Mathematical models have been made by Dingli and Michor that suggest that “successful therapy must eradicate cancer stem cells” (84).
The subject application concerns therapeutics operable for cancer treatment that function by modulating, reprogramming, conducting, and maintaining the growth and differentiation of normal and tumor cells by using biomodulators, instead of trying, like prior art cancer therapies do, to kill, destroy, remove, intoxicate, and irradiate all malignant cells.
Despite efforts to fight cancer, many malignant diseases that are of interest in this application continue to present major challenges to clinical oncology. Prostate cancer, for example, is the second most common cause of cancer deaths in men. Current treatment protocols rely primarily on hormonal manipulations. However, in spite of initial high response rates, patients often develop hormone-refractory tumors, leading to rapid disease progression with poor prognosis. Overall, the results of cytotoxic chemotherapy have been disappointing, indicating a long felt need for new approaches to treatment of advanced prostatic cancer. Other diseases resulting from abnormal cell replication, for example metastatic melanomas, brain tumors of glial origin (e.g., astrocytomas), and lung adenocarcinoma, are also highly aggressive malignancies with poor prognosis. The incidence of melanoma and lung adenocarcinoma has been increasing significantly in recent years. Surgical treatments of brain tumors often fail to remove all tumor tissues, resulting in recurrences. Systemic chemotherapy is hindered by blood barriers. Therefore, there is an urgent need for new approaches to the treatment of human malignancies including advanced prostatic, lung, colon, breast and cervical cancers; melanoma; and brain tumors.